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PDQ®
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This treatment information summary on childhood liver cancer is an overview of prognosis, diagnosis, classification, and treatment. The National Cancer Institute created the PDQ database to increase the availability of new treatment information and its use in treating patients. Information and references from the most recently published literature are included after review by pediatric oncology specialists.
Cancer in children and adolescents is rare. A team approach, incorporating the skills of the primary care physician, surgical specialists, radiation therapists, pediatric oncologists/hematologists, rehabilitation specialists, pediatric nurse specialists, and social workers, is imperative to ensure that patients receive the best treatment. In order for advances to be made in treating these patients, therapy is best delivered in the context of a clinical trial at a major medical center with expertise in treating children. Only through entry of all eligible children with cancer into appropriate, well-designed clinical trials will progress be made against these diseases. Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics.[1]
Liver cancer, a rare malignancy in children and adolescents, is divided into two groups: hepatoblastoma and hepatocellular carcinoma. The age of onset of liver cancer in children is related to the histology of the tumor. Hepatoblastomas usually occur before 3 years of age, whereas the incidence of hepatocellular carcinoma in the United States varies little with age between 0 and 19 years.[2] The overall survival rate for children with hepatoblastoma is 70% [3-5] but is only 25% for hepatocellular carcinoma.[6]
If the tumor is completely removed, the majority of patients survive, but only a minority of patients have lesions amenable to complete resection at diagnosis. The inability to completely remove the primary tumor or the presence of metastatic disease is associated with a poor outcome. Hepatoblastoma is most often unifocal, while hepatocellular carcinoma is often extensively invasive or multicentric. Therefore, resection is possible more often in hepatoblastoma than hepatocellular carcinoma, in which less than 30% are resectable.[7]
The majority of patients with either hepatoblastoma or hepatocellular carcinoma have a serum tumor marker, alpha-fetoprotein, that parallels disease activity. Lack of a significant decrease of alpha-fetoprotein levels with treatment may predict a poor response to therapy.[8] Absence of elevated alpha-fetoprotein may be a poor prognostic sign in hepatoblastoma; it is associated with the small-cell (anaplastic) histologic variant, which responds very poorly to therapy. Occasionally hepatoblastomas produce beta-human chorionic gonadotropin resulting in isosexual precocity. Severe osteopenia is not uncommon. Hepatoblastoma is part of the constellation of findings associated with the Beckwith-Wiedemann syndrome.[9] Loss of the allele of maternal origin at the 11p15.5 familial Beckwith-Wiedemann syndrome locus occurs in many hepatoblastomas. Thus, the genetic abnormality that results in Beckwith- Wiedemann may be directly involved in the pathogenesis in some cases of hepatoblastoma, and imprinting may play a role.[10,11] About 2% of children with hepatoblastoma have hemihypertrophy.[12] There is a clear association between hepatoblastoma and familial adenomatous polyposis (FAP); children in families that carry the FAP gene are at an increased risk for hepatoblastoma, although it occurs in less than 1% of FAP family members.[13-15] Childhood hepatoblastomas frequently have mutations in the beta-catenin gene, the function of which is closely related to FAP.[16] A relationship between very low birth weight and hepatoblastoma has been reported.[17,18]
Hepatocellular carcinoma is associated with hepatitis B and C infection,[19,20] especially in children with perinatally acquired virus. Therefore, widespread hepatitis B immunization may decrease the incidence of hepatocellular carcinoma.[21] Compared to adults, the incubation period from hepatitis virus infection to the genesis of hepatocellular carcinoma is extremely short in some children with perinatally acquired virus. Mutations in the Met/hepatocyte growth factor gene occur in childhood hepatocellular carcinoma and so this could be the mechanism that results in a shortened incubation period.[22] Several specific types of nonviral liver injury and cirrhosis in children are associated with hepatocellular carcinoma: tyrosinemia, biliary cirrhosis, and alpha-1-antitrypsin deficiency.
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The cells of the "adult"-type hepatocellular carcinoma are epithelial compared with a less differentiated embryonal appearance of hepatoblastoma. Hepatocellular carcinoma also differs from hepatoblastoma in that it often arises in a previously abnormal, cirrhotic liver. However, hepatocellular carcinomas in children, unlike adults, do not arise from cirrhotic livers. Both histologic types more commonly arise in the right lobe of the liver. The hepatocellular nature of the tumor cells may be demonstrated by the finding of AFP or alpha-1-antitrypsin. Analysis of patients with resectable hepatoblastoma has suggested that tumors characterized as having pure "fetal" histology have a better prognosis when compared with those having an admixture of more primitive and rapidly dividing embryonal components or other undifferentiated tissues.[1-3] In addition, a distinctive histologic variant of hepatocellular carcinoma has been described in the noncirrhotic livers of older children and young adults. Termed fibrolamellar carcinoma, it has been associated with an improved prognosis.[4-6]
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A staging system based on postsurgical extent of tumor and surgical resectability has been used in grouping children with liver cancer. This staging system is used to determine treatment.[1-4] Children diagnosed with stage I and II hepatoblastoma have a cure rate of greater than 90% compared to 60% for stage III and approximately 20% for stage IV. For children dignosed with hepatocellular carcinoma, the outlook is much worse and the prognosis for advanced disease is very poor.
No metastases, tumor completely resected.
No metastases, tumor grossly resected with microscopic residual disease (i.e., positive margins); or tumor rupture, or tumor spill at the time of surgery.
No distant metastases, tumor unresectable or resected with gross residual tumor, or positive lymph nodes
There are distant metastases regardless of the extent of liver involvement.
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Many of the improvements in survival in childhood cancer have been made using new therapies that have attempted to improve on the best available, accepted therapy. Clinical trials in pediatrics are designed to compare potentially better therapy with therapy that is currently accepted as standard. This comparison may be done in a randomized study of two treatment arms or by evaluating a single new treatment, comparing the results with those previously obtained with standard therapy.
Because of the relative rarity of cancer in children, all children with liver cancer should be considered for entry into a clinical trial. Treatment planning by a multidisciplinary team of cancer specialists with experience treating tumors of childhood is required to determine and implement optimum treatment. Involvement of surgeons with experience in pediatric liver resection is critical.
Historically, resection of the primary tumor has been required to cure malignant liver tumors in children. Preoperative chemotherapy can convert a nonresectable tumor to a resectable one. Chemotherapy in some cases is able to eradicate pulmonary metastases completely and eliminate multinodular tumor foci in the liver. Chemotherapy has been much more successful in the treatment of hepatoblastoma than in hepatocellular carcinoma.[1-4] In recent years, virtually all children with hepatoblastoma have been treated with chemotherapy, and in some centers, even children with resectable hepatoblastoma are treated with preoperative chemotherapy, which may reduce the incidence of surgical complications at the time of resection. In contrast, the current Intergroup protocol for treatment of children with hepatoblastoma does not treat stage I tumors of purely fetal histology with chemotherapy unless they develop progressive disease, and resection at the time of diagnosis is encouraged for all tumors amenable to resection without undue risk.[5]
Surgical resection of distant disease has also contributed to the cure of children with hepatoblastoma. Resection of pulmonary metastases is recommended when the number of metastases is limited [6] and is often performed at the same time as resection of the primary tumor. When possible, resection of areas of locally invasive disease, such as in the diaphragm, and of isolated brain metastasis is recommended.[7]
Radiation, even in combination with chemotherapy, has not cured unresectable tumors. However, there may be a role for radiation therapy in the management of incompletely resected hepatoblastoma.[2,8] The dose of radiation that can be safely delivered immediately following resection is limited by its impairment of liver regeneration.
Liver transplantation has been used with some success to treat unresectable hepatic tumors in children. A few children with adverse prognosis due to lymph node or pulmonary metastases have been cured by transplantation after chemotherapy resulted in control of the metastases.[9,10] Because late metastasis develops more commonly in hepatocellular carcinoma than hepatoblastoma, survival after liver transplant in those patients is lower. The fibrolamellar variant of hepatocellular carcinoma may have a better outcome with liver transplant than other hepatocellular carcinomas.[11] The designations in PDQ that treatments are "standard" or "under clinical evaluation" are not to be used as a basis for reimbursement determinations.
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Combination chemotherapy has been demonstrated to have significant benefit in children with hepatoblastoma. Cisplatin-based chemotherapy has resulted in a survival rate of greater than 90% for children with stage I and stage II disease.[1,2] In comparison, a survey of children with liver tumors treated prior to the consistent use of combination chemotherapy found that 45 of 78 patients with hepatoblastoma who had complete excision of the tumor survived.[3] A randomized clinical trial has demonstrated comparable efficacy with cisplatin/vincristine/fluorouracil and cisplatin/doxorubicin in the treatment of hepatoblastoma; the combination of cisplatin/vincristine/fluorouracil, however, resulted in considerably less toxicity.[4]
Treatment options:
Complete surgical excision followed by four courses of combination chemotherapy with cisplatin, vincristine, and fluorouracil or comparable combination chemotherapy.[2] Completely excised tumor of purely fetal histology may be treated with doxorubicin alone [4] or carefully followed without further therapy.[2]
In a randomized trial, 7 of 7 patients with stage I hepatocellular carcinoma survived, disease-free, after adjuvant cisplatin-based chemotherapy.[5] In a survey of childhood liver tumors treated prior to the consistent use of chemotherapy only 12 of 33 patients with hepatocellular carcinoma who had complete excision of the tumor survived.[3] It is probable that adjuvant chemotherapy does benefit children with completely resected hepatocellular carcinoma. Treatment with cisplatin and doxorubicin may be recommended as adjuvant therapy since these are active agents in the treatment of hepatocellular carcinoma. For additional information, refer to the PDQ summary on adult primary liver cancer.
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In approximately 75% of children and adolescents with initially unresectable hepatoblastoma, tumors can be rendered resectable with cisplatin-based preoperative chemotherapy, and 60%-65% will survive disease-free. A randomized clinical trial has demonstrated equal efficacy with cisplatin/vincristine/fluorouracil, or cisplatin/doxorubicin in the treatment of hepatoblastoma; the combination of cisplatin/vincristine/fluorouracil, however, resulted in considerably less toxicity.[1] A combination of ifosfamide, cisplatin, and doxorubicin has also been successfully used in the treatment of advanced-stage disease.[2] Patients whose tumors remain unresectable should be considered for alternative chemotherapy, such as high-dose cisplatin with etoposide,[3] radiation therapy,[4,5] direct hepatic infusion of chemotherapeutic agents,[6] or orthotopic liver transplantation.[7,8]
Under investigation: Combination chemotherapy with cisplatin/carboplatin.[9]
In a randomized trial, cisplatin/vincristine/fluorouracil with or without doxorubicin given by continuous infusion was ineffective in adequately treating unresectable hepatocellular carcinoma. Therapy failed in 23 of 26 patients with stage III disease.[10] No particular treatment for unresectable hepatocellular carcinoma has proved especially effective in the pediatric age group. Occasional patients may benefit from treatment with cisplatin/doxorubicin therapy, especially if localized hepatic tumor shrinks adequately to allow resection of disease. Several therapeutic options have produced successful outcomes in some adults with hepatocellular carcinoma, including cryosurgery, intratumoral injection of alcohol, radiotherapeutic approaches, and liver transplantation. For detailed information and references, refer to the PDQ summary on adult primary liver cancer.
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The outcome for hepatoblastoma that is metastatic at diagnosis is not good, but cure is possible in 25%-30% of patients.[1-3] If possible, stage IV patients with resected primary tumor should have any remaining pulmonary metastases surgically removed. A randomized clinical trial has demonstrated equal efficacy with cisplatin/vincristine/fluorouracil and cisplatin/doxorubicin in the treatment of hepatoblastoma; the combination of cisplatin/vincristine/fluorouracil, however, resulted in considerably less toxicity.[3] A combination of ifosfamide, cisplatin, and doxorubicin has also been successfully used in the treatment of advanced-stage disease.[4] Patients whose tumors remain unresectable should be considered for alternative chemotherapy, such as high-dose cisplatin with etoposide,[5] radiation therapy,[2,6] direct hepatic infusion of chemotherapeutic agents,[7] or, if metastatic disease is controlled, orthotopic liver transplantation.[8,9]
Treatment options:
Four courses of cisplatin/vincristine/fluorouracil followed by attempted complete tumor resection. If the tumor is completely removed, two postoperative courses of the same chemotherapy should be given. If the tumor is not resectable after four courses of chemotherapy, alternative therapies should be considered.
Under investigation: Cisplatin/carboplatin combination chemotherapy.[10]
Alternative therapies:
2. Radiation therapy followed by re-exploration if metastatic disease is controlled.
3. Chemoembolization by hepatic arterial infusion.
4. Orthotopic liver transplantation if metastatic disease is controlled.
5. Phase I or II clinical trials of chemotherapy.
In a randomized trial, cisplatin/vincristine/fluorouracil with or without doxorubicin given by continuous infusion was ineffective in adequately treating unresectable hepatocellular carcinoma. Therapy failed in 12 of 13 patients with stage IV disease.[11] No particular treatment for unresectable hepatocellular carcinoma has proved especially effective in the pediatric age group. Occasional patients may benefit from treatment with cisplatin/doxorubicin therapy, especially if localized hepatic tumor shrinks adequately to allow resection of disease. For additional information, refer to the PDQ summary on adult primary liver cancer.
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The prognosis for a patient with recurrent or progressive hepatoblastoma depends on many factors, including the site of recurrence, prior treatment, and individual patient considerations. For example, in patients with stage I hepatoblastoma at initial diagnosis, aggressive surgical treatment of isolated pulmonary metastases that develop in the course of the disease may make extended disease-free survival possible.[1] If possible, isolated metastases should be resected completely in patients whose primary tumor is controlled.[2] Phase I and II clinical trials may be appropriate and should be considered.
The prognosis for a patient with recurrent or progressive hepatocellular carcinoma is poor. Phase I and II clinical trials may be appropriate and should be considered. Refer to the PDQ summary on adult primary liver cancer for details.
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Date Last Modified: 11/1999
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Treatment